The invention refers to a process for obtaining the pure polymorphic form of finasteride called Form I.
Finasteride [5α,17β)-N-(1,1-dimethylethyl)-3-oxo-4-aza-androst-1-ene-17-carboxamide] is an inhibitor of 5-α-reductase, an enzyme which reduces testosterone to dihydrotestosterone (DHT) which is the main mediator of the androgenic activity in some organs. Finasteride can prevent or reduce the symptoms of hyperandrogenic stimulation and is used as a drug substance in multiple therapeutic applications, such as in the treatment of benign prostate hyperplasia and androgenic alopecia.
Several processes for obtaining finasteride are known [see, for example, U.S. Pat. Nos. 4,377,584, 4,760,071, 5,084,574, 5,116,983 or International patent application WO 01/02422].
Finasteride can exist in several different polymorphic forms [see, for example, European patent EP 0 599 376 B1, International patent application WO 02/20553 A1 or the scientific publication Journal of Molecular Structure, 474, 157-166 (1999)], among which are those called Form I and Form II, which differ from each other in their crystalline structure. The different crystalline structures which a compound can have lead to a variation in its physicochemical parameters, such as stability, dissolution rate, solubility, melting point, etc. This variation in the properties of the compound is translated into a different bioavailability thereof, especially in those cases in which the drug substance is supplied in solid form.
From the pharmaceutical point of view, it is very important to have single and pure crystalline forms for the elaboration of pure pharmaceutical forms complying with the required pure pharmaceutical product specifications. The obtainment of single crystalline forms solves the lack of reproducibility and different bioavailability problems which pharmaceutical forms have when mixtures of polymorphs are used. Different polymorphic forms can be obtained by controlling crystallization conditions.
In the particular case of finasteride, the marketed polymorphic form is Form I, which constitutes the drug substance in the medicinal product called Proscar®.
U.S. Pat. No. 5,652,365 and EP 0 599 376 B1 disclose the preparation of the polymorphic forms Form I and Form II of finasteride. Particularly, EP 0 599 376 B1 claims a process for obtaining Form I of finasteride comprising the crystallization of said Form I from ethyl acetate with a water content of up to 3.5 mg/mL, or from isopropyl acetate with a water content of up to 1.6 mg/mL at room temperature.
Patent GB 2,338,234 discloses a process for preparing Form I of finasteride comprising initial formation of a substantially insoluble complex formed by finasteride and a salt of a Group I or Group II metal of the periodic table of elements, such as lithium bromide, in the presence of a hydroxylic solvent followed by dissociation of the complex by dissolution with acidified water and recovery of the crystalline Form I of finasteride.